bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019–01–13
48 papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
  2. Mitochondrial complex III is essential for suppressive function of regulatory T cells.
  3. Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies.
  4. Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers.
  5. Cardiolipin-dependent mitophagy guides outcome after traumatic brain injury.
  6. Mitochondrial proteins: from biogenesis to functional networks.
  7. RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway.
  8. Heterozygous knockout insulin-like growth factor-1 receptor (IGF-1R) regulates mitochondrial functions and prevents colitis and colorectal cancer.
  9. Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.
  10. A Mammalian Mitophagy Receptor, Bcl2-L-13, Recruits the ULK1 Complex to Induce Mitophagy.
  11. The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.
  12. IDH3α regulates one-carbon metabolism in glioblastoma.
  13. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma.
  14. Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells.
  15. Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics.
  16. Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism.
  17. Parkin overexpression protects from aging-related loss of muscle mass and strength.
  18. Transmission of Dysfunctional Mitochondrial DNA and Its Implications for Mammalian Reproduction.
  19. RNase H1 promotes replication fork progression through oppositely transcribed regions of Drosophila mitochondrial DNA.
  20. Impaired autophagic and mitochondrial functions are partially restored by ERT in Gaucher and Fabry diseases.
  21. Cardiac-specific deficiency of the mitochondrial calcium uniporter augments fatty acid oxidation and functional reserve.
  22. High intensity exercise inhibits carnitine palmitoyltransferase-I sensitivity to L-carnitine.
  23. The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier.
  24. Calcium phosphate precipitation inhibits mitochondrial energy metabolism.
  25. Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function.
  26. NAD Metabolism in Cancer Therapeutics.
  27. Nutrient Regulation of Signaling & Transcription.
  28. Increased Dynamin-Related Protein 1-Dependent Mitochondrial Fission Contributes to High-Fat Diet-Induced Cardiac Dysfunction and Insulin Resistance by Elevating Tafazzin in Mouse Hearts.
  29. The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons.
  30. Strangers in strange lands: mitochondrial proteins found at extra-mitochondrial locations.
  31. Glutaminolysis Mediated by MALT1 Protease Activity Facilitates PD-L1 Expression on ABC-DLBCL Cells and Contributes to Their Immune Evasion.
  32. Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis.
  33. Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2+/- Mice.
  34. Improving the metabolic fidelity of cancer models with a physiological cell culture medium.
  35. Signaling and Regulation of the Mitochondrial Unfolded Protein Response.
  36. HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance.
  37. Calcium signalling in T cells.
  38. Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences.
  39. Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
  40. Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study.
  41. Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin.
  42. METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
  43. AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth.
  44. Spatially Stable Mitochondrial Compartments Fuel Local Translation during Plasticity.
  45. Natural Killer Cell Education Is Associated With a Distinct Glycolytic Profile.
  46. Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo.
  47. Fat cells with a sweet tooth.
  48. Analyzing cysteine site neighbors in proteins to reveal dimethyl fumarate targets.
  1. Oncogene. 2019 Jan 09.
    The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
    Katarzyna Parzych, Paula Saavedra-García, Gabriel N Valbuena, Hibah A Al-Sadah, Mark E Robinson, Lucy Penfold, Desislava M Kuzeva, Angie Ruiz-Tellez, Sandra Loaiza, Viktoria Holzmann, Valentina Caputo, David C Johnson, Martin F Kaiser, Anastasios Karadimitris, Eric W-F Lam, Eric Chevet, Niklas Feldhahn, Hector C Keun, Holger W Auner.
      VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
    DOI:  https://doi.org/10.1038/s41388-018-0651-z
  2. Nature. 2019 Jan 09.
    Mitochondrial complex III is essential for suppressive function of regulatory T cells.
    Samuel E Weinberg, Benjamin D Singer, Elizabeth M Steinert, Carlos A Martinez, Manan M Mehta, Inmaculada Martínez-Reyes, Peng Gao, Kathryn A Helmin, Hiam Abdala-Valencia, Laura A Sena, Paul T Schumacker, Laurence A Turka, Navdeep S Chandel.
      Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
    DOI:  https://doi.org/10.1038/s41586-018-0846-z
  3. Am J Physiol Cell Physiol. 2019 Jan 09.
    Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies.
    Sofhia V Ramos, Meghan C Hughes, Christopher G R Perry.
      Microtubule-targeting chemotherapies are linked to impaired cellular metabolism which may contribute to skeletal muscle dysfunction. However, the mechanisms by which metabolic homeostasis is perturbed remains unknown. Tubulin, the fundamental unit of microtubules, has been implicated in the regulation of mitochondrial-cytosolic ADP/ATP exchange through its interaction with the outer membrane voltage-dependent anion channel (VDAC). Based on this model, we predicted that disrupting microtubule architecture with the stabilizer paclitaxel and destabilizer vinblastine would impair skeletal muscle mitochondrial bioenergetics. Here we provide in-vitro evidence of a direct interaction between both a-tubulin and bII-tubulin with VDAC2 in un-treated single extensor digitorum longus fibres. Paclitaxel increased both a- and bII-tubulin-VDAC2 interactions whereas vinblastine had no effect. Utilizing a permeabilized muscle fiber bundle preparation that retains the cytoskeleton, paclitaxel treatment impaired the ability of ADP to attenuate H2O2 emission, resulting in greater H2O2 emission kinetics. Despite no effect on tubulin-VDAC2 binding, vinblastine still altered mitochondrial bioenergetics through a surprising increase in ADP-stimulated respiration while also impairing ADP-suppression of H2O2 and increasing mitochondrial susceptibility to calcium-induced formation of the pro-apoptotic permeability transition pore. Collectively, these results demonstrate that altering microtubule architecture with chemotherapeutics disrupts mitochondrial bioenergetics in skeletal muscle. Altered tubulin-VDAC binding with paclitaxel supports the model that microtubules regulate mitochondria by altering ADP's governance of bioenergetics, whereas vinblastine may act through an alternative mechanism associated with decreased microtubule abundance in skeletal muscle.
    Keywords:  Chemotherapy; Microtubule; Mitochondria; Paclitaxel; Vinblastine
    DOI:  https://doi.org/10.1152/ajpcell.00384.2018
  4. J Clin Invest. 2019 Jan 07. pii: 120855. [Epub ahead of print]
    Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers.
    John C Chappell, Laura Beth Payne, W Kimryn Rathmell.
      The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
    DOI:  https://doi.org/10.1172/JCI120855
  5. J Neurosci. 2019 Jan 09. pii: 3415-17. [Epub ahead of print]
    Cardiolipin-dependent mitophagy guides outcome after traumatic brain injury.
    Honglu Chao, Chao Lin, Qiang Zuo, Yinlong Liu, Mengqing Xiao, Xiupeng Xu, Zheng Li, Zhongyuan Bao, Huimei Chen, Yongping You, Patrick M Kochanek, Huiyong Yin, Ning Liu, Valerian E Kagan, Hülya Bayır, Jing Ji.
      Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Taken together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.SIGNIFICANCE STATEMENTTBI increases energy demands leading to activation of mitochondrial respiration associated with enhanced generation of reactive oxygen species and resultant damage to mitochondria. We demonstrate that the complete elimination of irreparably damaged organelles via mitophagy is activated as an early response to TBI. This response includes translocation of mitochondria phospholipid CL from the inner membrane to the outer membrane where externalized cardiolipin mediates targeted LC3-mediated autophagy of damaged mitochondria. Our data on targeting phospholipid scramblase and cardiolipin synthase in genetically manipulated cells and animals strongly support the essential role of cardiolipin externalization mechanisms in the endogenous reparative plasticity of injured brain cells. Furthermore, successful execution and completion of mitophagy is beneficial in the context of preservation of cognitive functions after TBI.
    DOI:  https://doi.org/10.1523/JNEUROSCI.3415-17.2018
  6. Nat Rev Mol Cell Biol. 2019 Jan 09.
    Mitochondrial proteins: from biogenesis to functional networks.
    Nikolaus Pfanner, Bettina Warscheid, Nils Wiedemann.
      Mitochondria are essential for the viability of eukaryotic cells as they perform crucial functions in bioenergetics, metabolism and signalling and have been associated with numerous diseases. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. In this Review, we discuss the emerging role of the mitochondrial protein import machinery as a key organizer of these mitochondrial protein networks. The preprotein translocases that reside on the mitochondrial membranes not only function during organelle biogenesis to deliver newly synthesized proteins to their final mitochondrial destination but also cooperate with numerous other mitochondrial protein complexes that perform a wide range of functions. Moreover, these protein networks form membrane contact sites, for example, with the endoplasmic reticulum, that are key for integration of mitochondria with cellular function, and defects in protein import can lead to diseases.
    DOI:  https://doi.org/10.1038/s41580-018-0092-0
  7. Sci Adv. 2018 Nov;4(11): eaav0443
    RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway.
    J-M Heo, A Ordureau, S Swarup, J A Paulo, K Shen, D M Sabatini, J W Harper.
      Removal of damaged mitochondria is orchestrated by a pathway involving the PINK1 kinase and the PARKIN ubiquitin ligase. Ubiquitin chains assembled by PARKIN on the mitochondrial outer membrane recruit autophagy cargo receptors in complexes with TBK1 protein kinase. While TBK1 is known to phosphorylate cargo receptors to promote ubiquitin binding, it is unknown whether TBK1 phosphorylates other proteins to promote mitophagy. Using global quantitative proteomics, we identified S72 in RAB7A, a RAB previously linked with mitophagy, as a dynamic target of TBK1 upon mitochondrial depolarization. TBK1 directly phosphorylates RAB7AS72, but not several other RABs known to be phosphorylated on the homologous residue by LRRK2, in vitro, and this modification requires PARKIN activity in vivo. Interaction proteomics using nonphosphorylatable and phosphomimetic RAB7A mutants revealed loss of association of RAB7AS72E with RAB GDP dissociation inhibitor and increased association with the DENN domain-containing heterodimer FLCN-FNIP1. FLCN-FNIP1 is recruited to damaged mitochondria, and this process is inhibited in cells expressing RAB7AS72A. Moreover, nonphosphorylatable RAB7A failed to support efficient mitophagy, as well as recruitment of ATG9A-positive vesicles to damaged mitochondria. These data reveal a novel function for TBK1 in mitophagy, which parallels that of LRRK2-mediated phosphorylation of the homologous site in distinct RABs to control membrane trafficking.
    DOI:  https://doi.org/10.1126/sciadv.aav0443
  8. Free Radic Biol Med. 2019 Jan 03. pii: S0891-5849(18)31556-9. [Epub ahead of print]134 87-98
    Heterozygous knockout insulin-like growth factor-1 receptor (IGF-1R) regulates mitochondrial functions and prevents colitis and colorectal cancer.
    Shu Qing Wang, Xiang Yu Yang, Shu Xiang Cui, Zu Hua Gao, Xian Jun Qu.
      Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r+/- mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r+/- mice. Seahorse XFe-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/- cells. Further analysis suggests the protection mechanisms of Igf1r+/- cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.
    Keywords:  Colitis-associated cancer; IGF-1R; LKB1/AMPK pathways; Mitochondrial functions; Oxidative stress; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2018.12.035
  9. Cell Rep. 2019 Jan 08. pii: S2211-1247(18)31973-9. [Epub ahead of print]26(2): 469-482.e5
    Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.
    Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher A Bristow, Alessandro Carugo, Norma Rogers, Paul Leonard, Qing Chang, Robert Mullinax, Jing Han, Xi Shi, Sahil Seth, Brooke A Meyers, Meredith Miller, Lili Miao, Xiaoyan Ma, Ningping Feng, Virginia Giuliani, Mary Geck Do, Barbara Czako, Wylie S Palmer, Faika Mseeh, John M Asara, Yongying Jiang, Pietro Morlacchi, Shuping Zhao, Michael Peoples, Trang N Tieu, Marc O Warmoes, Philip L Lorenzi, Florian L Muller, Ronald A DePinho, Giulio F Draetta, Carlo Toniatti, Philip Jones, Timothy P Heffernan, Joseph R Marszalek.
      The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.
    Keywords:  OXPHOS; PGD; fumarate hydratase; functional genomics; hereditary leiomyomatosis renal cell carcinoma; metabolic vulnerability; pentose phosphate pathway; redox homeostasis; synthetic lethality; tumor metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2018.12.043
  10. Cell Rep. 2019 Jan 08. pii: S2211-1247(18)31980-6. [Epub ahead of print]26(2): 338-345.e6
    A Mammalian Mitophagy Receptor, Bcl2-L-13, Recruits the ULK1 Complex to Induce Mitophagy.
    Tomokazu Murakawa, Koji Okamoto, Shigemiki Omiya, Manabu Taneike, Osamu Yamaguchi, Kinya Otsu.
      Degradation of mitochondria by selective autophagy, termed mitophagy, contributes to the control of mitochondrial quality. Bcl2-L-13 is a mammalian homolog of Atg32, which is an essential mitophagy receptor in yeast. However, the molecular machinery involved in Bcl2-L-13-mediated mitophagy remains to be elucidated. Here, we show that the ULK1 (unc-51-like kinase) complex is required for Bcl2-L-13 to process mitophagy. Screening of a series of yeast Atg mutants revealed that a different set of ATG genes is used for Bcl2-L-13- and Atg32-mediated mitophagy in yeast. The components of the Atg1 complex essential for starvation-induced autophagy were indispensable in Bcl2-L-13-, but not Atg32-mediated, mitophagy. The ULK1 complex, a counterpart of the Atg1 complex, is necessary for Bcl2-L-13-mediated mitophagy in mammalian cells. We propose a model where, upon mitophagy induction, Bcl2-L-13 recruits the ULK1 complex to process mitophagy and the interaction of LC3B with ULK1, as well as Bcl2-L-13, is important for the mitophagy.
    Keywords:  Atg32; Bcl2-L-13; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2018.12.050
  11. Nat Commun. 2019 Jan 08. 10(1): 83
    The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.
    S A Baechler, V M Factor, I Dalla Rosa, A Ravji, D Becker, S Khiati, L M Miller Jenkins, M Lang, C Sourbier, S A Michaels, L M Neckers, H L Zhang, A Spinazzola, S N Huang, J U Marquardt, Y Pommier.
      Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.
    DOI:  https://doi.org/10.1038/s41467-018-07922-3
  12. Sci Adv. 2019 Jan;5(1): eaat0456
    IDH3α regulates one-carbon metabolism in glioblastoma.
    Jasmine L May, Fotini M Kouri, Lisa A Hurley, Juan Liu, Serena Tommasini-Ghelfi, Yanrong Ji, Peng Gao, Andrea E Calvert, Andrew Lee, Navdeep S Chandel, Ramana V Davuluri, Craig M Horbinski, Jason W Locasale, Alexander H Stegh.
      Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity, S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.
    DOI:  https://doi.org/10.1126/sciadv.aat0456
  13. Cancer Res. 2019 Jan 08. pii: canres.0773.2018. [Epub ahead of print]
    CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma.
    Christopher R Marlein, Rachel E Piddock, Jayna J Mistry, Lyubov Zaitseva, Charlotte Hellmich, Rebecca H Horton, Zhigang Zhou, Martin J Auger, Kristian M Bowles, Stuart A Rushworth.
      Metabolic adjustments are necessary for the initiation, proliferation, and spread of cancer cells. Although mitochondria have been shown to move to cancer cells from their microenvironment, the metabolic consequences of this phenomenon have yet to be fully elucidated. Here we report that multiple myeloma (MM) cells use mitochondrial-based metabolism as well as glycolysis when located within the bone marrow microenvironment (BMM). The reliance of MM cells on oxidative phosphorylation was caused by intercellular mitochondrial transfer to MM cells from neighboring non-malignant bone marrow stromal cells (BMSC). This mitochondrial transfer occurred through tumor-derived tunneling nanotubes (TNT). Moreover, shRNA mediated knockdown of CD38 inhibits mitochondrial transfer and TNT formation in-vitro and blocks mitochondrial transfer and improves animal survival in vivo. This study describes a potential treatment strategy to inhibit mitochondrial transfer for clinical benefit and scientifically expands the understanding of the functional effects of mitochondrial transfer on tumor metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-0773
  14. Stem Cells. 2019 Jan 10.
    Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells.
    Kelli I Korski, Dieter A Kubli, Bingyan J Wang, Farid G Khalafalla, Megan M Monsanto, Fareheh Firouzi, Oscar H Echeagaray, Taeyong Kim, Robert M Adamson, Walter P Dembitsky, Åsa B Gustafsson, Mark A Sussman.
      Senescence-associated dysfunction deleteriously affects biological activites of human c-Kit+ cardiac progenitor cells (hCPCs), particularly under conditions of in vitro culture. In comparison, preservation of self-renewal and decreases in mitochondrial reactive oxygen species (ROS) are characteristic of murine CPCs in vivo that reside within hypoxic niches. Recapitulating hypoxic niche oxygen tension conditions of ~1% O2 in vitro for expansion of hCPCs rather than typical normoxic cell culture conditions (21% O2 ) could provide significant improvement of functional and biological activity of hCPCs. hCPCs were isolated and expanded under permanent hypoxia (hCPC-1%) or normoxia (hCPC-21%) from left ventricular tissue explants collected during left ventricular assist device implantation. hCPC-1% exhibit increased self-renewal and suppression of senescence characteristics relative to hCPC-21%. Oxidative stress contributed to higher susceptibility to apoptosis, as well as decreased mitochondrial function in hCPC-21%. Hypoxia prevented accumulation of dysfunctional mitochondria, supporting higher oxygen consumption rates and mitochondrial membrane potential. Mitochondrial ROS was an upstream mediator of senescence since treatment of hCPC-1% with mitochondrial inhibitor antimycin A recapitulated mitochondrial dysfunction and senescence observed in hCPC-21%. NAD+ /NADH ratio and autophagic flux, key factors for mitochondrial function, were higher in hCPC-1%, but hCPC-21% were highly dependent on BNIP3/NIX-mediated mitophagy to maintain mitochondrial function. Collectively, results demonstrate that supraphysiological oxygen tension during in vitro expansion initiates a downward spiral of oxidative stress, mitochondrial dysfunction, and cellular energy imbalance culminating in early proliferation arrest of hCPCs. Senescence is inhibited by preventing ROS through hypoxic culture of hCPCs. SIGNIFICANCE STATEMENT: hCPC biological function is hampered by limited expansion potential and early replicative senescence. Permanent hypoxia (1% O2 ) preserved clonogenicity and mitochondrial function of hCPC derived from heart failure (HF) patients while maintaining high levels of intracellular NAD+ /NADH ratio and suppressing ROS and oxidative stress. © AlphaMed Press 2019.
    Keywords:  ROS; autophagy; heart; human; mitochondria; stem cells
    DOI:  https://doi.org/10.1002/stem.2970
  15. Nat Commun. 2019 Jan 10. 10(1): 104
    Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics.
    Zhen Chen, Caoqi Lei, Chao Wang, Nan Li, Mrinal Srivastava, Mengfan Tang, Huimin Zhang, Jong Min Choi, Sung Yun Jung, Jun Qin, Junjie Chen.
      AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis. Although AMPK has been studied extensively in cellular processes, understanding of its substrates and downstream functional network, and their contributions to cell fate and disease development, remains incomplete. To elucidate the AMPK-dependent signaling pathways, we performed global quantitative phosphoproteomic analysis using wild-type and AMPKα1/α2-double knockout cells and discovered 160 AMPK-dependent phosphorylation sites. Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion.
    DOI:  https://doi.org/10.1038/s41467-018-08004-0
  16. Oncogene. 2019 Jan 11.
    Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism.
    Jasdeep Mann, John Maringa Githaka, Timothy W Buckland, Ning Yang, Rachel Montpetit, Namrata Patel, Lei Li, Shairaz Baksh, Roseline Godbout, Hélène Lemieux, Ing Swie Goping.
      The Bcl-2-associated death promoter BAD is a prognostic indicator for good clinical outcome of breast cancer patients; however, whether BAD affects breast cancer biology is unknown. Here we showed that BAD increased cell growth in breast cancer cells through two distinct mechanisms. Phosphorylation of BAD at S118 increased S99 phosphorylation, 14-3-3 binding and AKT activation to promote growth and survival. Through a second, more prominent pathway, BAD stimulated mitochondrial oxygen consumption in a novel manner that was downstream of substrate entry into the mitochondria. BAD stimulated complex I activity that facilitated enhanced cell growth and sensitized cells to apoptosis in response to complex I blockade. We propose that this dependence on oxidative metabolism generated large but nonaggressive cancers. This model identifies a non-canonical role for BAD and reconciles BAD-mediated tumor growth with favorable outcomes in BAD-high breast cancer patients.
    DOI:  https://doi.org/10.1038/s41388-018-0673-6
  17. J Physiol. 2019 Jan 07.
    Parkin overexpression protects from aging-related loss of muscle mass and strength.
    Jean-Philippe Leduc-Gaudet, Olivier Reynaud, Sabah N Hussain, Gilles Gouspillou.
       KEY POINTS: Recent evidence suggests that impaired mitophagy, a process in charge of removing damaged/dysfunctional mitochondria and in part regulated by Parkin, could contribute to the aging-related loss of muscle mass and function. Here, we show that parkin overexpression attenuates aging-related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects from aging-related increases in markers of oxidative stress, fibrosis and apoptosis. Our findings place Parkin as a potential therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance. The aging-related loss of muscle mass and strength, a process called sarcopenia, is one of the most deleterious hallmarks of aging. Solid experimental evidence indicates that mitochondrial dysfunctions accumulate with aging and are critical in the sarcopenic process. Recent findings suggest that mitophagy, the process in charge of the removal of damaged/dysfunctional mitochondria, is altered in aged muscle. Impaired mitophagy represents an attractive mechanism that could contribute to the accumulation of mitochondrial dysfunctions and sarcopenia. To test this hypothesis, we investigated the impact of Parkin overexpression in skeletal muscles of young and old mice. Parkin was overexpressed for 4 months in muscles of young (3mo) and late middle-aged (18mo) mice using intramuscular injections of Adeno-Associated Viruses. We show that Parkin overexpression increased muscle mass, fiber size and mitochondrial enzyme activities in both young and old muscles. In old mice, Parkin overexpression increased muscle strength, PGC-1α content and mitochondrial density. Parkin overexpression also attenuated the aging-related increase in 4-hydroxynonenal content (a marker of oxidative stress), type I collagen content (a marker of fibrosis) and in the number of TUNEL-positive myonuclei (a marker of apoptosis). Overall, our results indicate Parkin overexpression attenuates sarcopenia and unexpectedly causes hypertrophy in adult muscles. They also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects against oxidative stress, fibrosis and apoptosis. These findings highlight that Parkin may be an attractive therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance. This article is protected by copyright. All rights reserved.
    Keywords:  Apoptosis; Mitochondrial biogenesis; Mitophagy; Muscle atrophy; Muscle hypertrophy; Oxidative Stress; Sarcopenia
    DOI:  https://doi.org/10.1113/JP277157
  18. Adv Anat Embryol Cell Biol. 2019 Jan 09.
    Transmission of Dysfunctional Mitochondrial DNA and Its Implications for Mammalian Reproduction.
    Kanokwan Srirattana, Justin C St John.
      Mitochondrial DNA (mtDNA) encodes proteins for the electron transport chain which produces the vast majority of cellular energy. MtDNA has its own replication and transcription machinery that relies on nuclear-encoded transcription and replication factors. MtDNA is inherited in a non-Mendelian fashion as maternal-only mtDNA is passed onto the next generation. Mutation to mtDNA can cause mitochondrial dysfunction, which affects energy production and tissue and organ function. In somatic cell nuclear transfer (SCNT), there is an issue with the mixing of two populations of mtDNA, namely from the donor cell and recipient oocyte. This review focuses on the transmission of mtDNA in SCNT embryos and offspring. The transmission of donor cell mtDNA can be prevented by depleting the donor cell of its mtDNA using mtDNA depletion agents prior to SCNT. As a result, SCNT embryos harbour oocyte-only mtDNA. Moreover, culturing SCNT embryos derived from mtDNA depleted cells in media supplemented with a nuclear reprograming agent can increase the levels of expression of genes related to embryo development when compared with non-depleted cell-derived embryos. Furthermore, we have reviewed how mitochondrial supplementation in oocytes can have beneficial effects for SCNT embryos by increasing mtDNA copy number and the levels of expression of genes involved in energy production and decreasing the levels of expression of genes involved in embryonic cell death. Notably, there are beneficial effects of mtDNA supplementation over the use of nuclear reprograming agents in terms of regulating gene expression in embryos. Taken together, manipulating mtDNA in donor cells and/or oocytes prior to SCNT could enhance embryo production efficiency.
    Keywords:  Embryo; Mitochondrial DNA; Mitochondrial supplementation; Replication; Somatic cell nuclear transfer; Transmission
    DOI:  https://doi.org/10.1007/102_2018_3
  19. J Biol Chem. 2019 Jan 11. pii: jbc.RA118.007015. [Epub ahead of print]
    RNase H1 promotes replication fork progression through oppositely transcribed regions of Drosophila mitochondrial DNA.
    Jose M González de Cózar, Mike Gerards, Eveliina Teeri, Jack George, Eric Dufour, Howard T Jacobs, Priit Jõers.
      Mitochondrial DNA (mtDNA) replication uses a simple core machinery similar to those of bacterial viruses and plasmids, but its components are challenging to unravel. Here we found that, as in mammals, the single Drosophila gene for RNase H1 (rnh1) has alternative translational start sites, resulting in two polypeptides, targeted to either mitochondria or the nucleus. RNAi-mediated rnh1 knockdown did not influence growth or viability of S2 cells, but compromised mtDNA integrity and copy number. rnh1 knockdown in intact flies also produced a phenotype of impaired mitochondrial function, characterized by respiratory chain deficiency, locomotor dysfunction and decreased lifespan. Its over-expression in S2 cells resulted in cell-lethality after 5-9 days, attributable to the nuclear-localized isoform. rnh1 knockdown and over-expression produced opposite effects on mtDNA replication intermediates. The most pronounced effects were seen in genome regions beyond the major replication pauses, where the replication fork needs to progress through a gene cluster that is transcribed in the opposite direction. RNase H1 deficiency led to an accumulation of replication intermediates in these zones, abundant mtDNA molecules joined by 4-way junctions, and species consistent with fork regression from the origin. These findings indicate replication stalling due to the presence of unprocessed RNA/DNA heteroduplexes, potentially leading to the degradation of collapsed forks or to replication restart by a mechanism involving strand invasion. Both mitochondrial RNA and DNA syntheses were affected by rnh1 knockdown, suggesting that RNase H1 also plays a role in integrating or co-regulating these processes in Drosophila mitochondria.
    Keywords:  DNA replication; RNA; RNase H; genomic instability; heteroduplex; locomotor dysfunction; mitochondria; mtDNA; replication fork; ribonuclease
    DOI:  https://doi.org/10.1074/jbc.RA118.007015
  20. PLoS One. 2019 ;14(1): e0210617
    Impaired autophagic and mitochondrial functions are partially restored by ERT in Gaucher and Fabry diseases.
    Margarita M Ivanova, Erk Changsila, Chidima Iaonou, Ozlem Goker-Alpan.
      The major cellular clearance pathway for organelle and unwanted proteins is the autophagy-lysosome pathway (ALP). Lysosomes not only house proteolytic enzymes, but also traffic organelles, sense nutrients, and repair mitochondria. Mitophagy is initiated by damaged mitochondria, which is ultimately degraded by the ALP to compensate for ATP loss. While both systems are dynamic and respond to continuous cellular stressors, most studies are derived from animal models or cell based systems, which do not provide complete real time data about cellular processes involved in the progression of lysosomal storage diseases in patients. Gaucher and Fabry diseases are rare sphingolipid disorders due to the deficiency of the lysosomal enzymes; glucocerebrosidase and α-galactosidase A with resultant lysosomal dysfunction. Little is known about ALP pathology and mitochondrial function in patients with Gaucher and Fabry diseases, and the effects of enzyme replacement therapy (ERT). Studying blood mononuclear cells (PBMCs) from patients, we provide in vivo evidence, that regulation of ALP is defective. In PBMCs derived from Gaucher patients, we report a decreased number of autophagic vacuoles with increased cytoplasmic localization of LC3A/B, accompanied by lysosome accumulation. For both Gaucher and Fabry diseases, the level of the autophagy marker, Beclin1, was elevated and ubiquitin binding protein, SQSTM1/p62, was decreased. mTOR inhibition did not activate autophagy and led to ATP inhibition in PBMCs. Lysosomal abnormalities, independent of the type of the accumulated substrate suppress not only autophagy, but also mitochondrial function and mTOR signaling pathways. ERT partially restored ALP function, LC3-II accumulation and decreased LC3-I/LC3-II ratios. Levels of lysosomal (LAMP1), autophagy (LC3), and mitochondrial markers, (Tfam), normalized after ERT infusion. In conclusion, there is mTOR pathway dysfunction in sphingolipidoses, as observed in both PBMCs derived from patients with Gaucher and Fabry diseases, which leads to impaired autophagy and mitochondrial stress. ERT partially improves ALP function.
    DOI:  https://doi.org/10.1371/journal.pone.0210617
  21. J Mol Cell Cardiol. 2019 Jan 04. pii: S0022-2828(18)31211-2. [Epub ahead of print]
    Cardiac-specific deficiency of the mitochondrial calcium uniporter augments fatty acid oxidation and functional reserve.
    Tariq R Altamimi, Qutuba G Karwi, Golam Mezbah Uddin, Arata Fukushima, Jennifer Q Kwong, Jeffery D Molkentin, Gary D Lopaschuk.
      The mitochondrial calcium uniporter (MCU) relays cytosolic Ca2+ transients to the mitochondria. We examined whether energy metabolism was compromised in hearts from mice with a cardiac-specific deficiency of MCU subjected to an isoproterenol (ISO) challenge. Surprisingly, isolated working hearts from cardiac MCU-deficient mice showed higher cardiac work, both in the presence or absence of ISO. These hearts were not energy-starved, with ISO inducing a similar increase in glucose oxidation rates compared to control hearts, but a greater increase in fatty acid oxidation rates. This correlated with lower levels of the fatty acid oxidation inhibitor malonyl CoA, and to an increased stimulatory acetylation of its degrading enzyme malonyl CoA decarboxylase and of the fatty acid β-oxidation enzyme β-hydroxyacyl CoA dehydrogenase. We conclude that impaired mitochondrial Ca2+ uptake does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation that provides a higher energy reserve during acute adrenergic stress.
    Keywords:  Fatty acid oxidation; Glucose oxidation; High workload; Lysine acetylation; Malonyl CoA; Mitochondrial calcium uniporter
    DOI:  https://doi.org/10.1016/j.yjmcc.2018.12.019
  22. Biochem J. 2019 Jan 11. pii: BCJ20180849. [Epub ahead of print]
    High intensity exercise inhibits carnitine palmitoyltransferase-I sensitivity to L-carnitine.
    Heather L Petrick, Graham P Holloway.
      The decline in fat oxidation at higher power outputs of exercise is a complex interaction between several mechanisms, however the influence of mitochondrial bioenergetics in this process remains elusive. Therefore, using permeabilized muscle fibers from mouse skeletal muscle, we aimed to determine if acute exercise altered mitochondrial sensitivity to 1) adenosine diphosphate (ADP) and inorganic phosphate (Pi), or 2) carnitine palmitoyltransferase-I (CPT-I) independent (palmitoylcarnitine, PC) and dependent (palmitoyl-CoA (P-CoA), malonyl-CoA (M-CoA), and L-carnitine) substrates, in an intensity-dependent manner. As the apparent ADP Km increased to a similar extent following low (LI) and high (HI) intensity exercise compared to sedentary (SED) animals, and Pi sensitivity was unaltered by exercise, regulation of phosphate provision likely does not contribute to the well-established intensity-dependent shift in substrate utilization. Mitochondrial sensitivity to PC and P-CoA were not influenced by exercise, while M-CoA sensitivity was attenuated similarly following LI and HI. In contrast, CPT-I sensitivity to L-carnitine was only altered following HI, as HI exercise attenuated L-carnitine sensitivity by ~40%. Moreover, modelling the in vivo concentrations of L-carnitine and P-CoA during exercise suggest that CPT-I flux is ~25% lower following HI, attributed equally to reductions in L-carnitine content and L-carnitine sensitivity. Altogether, these data further implicate CPT-I flux as a key event influencing metabolic interactions during exercise, as a decline in L-carnitine sensitivity in addition to availability at higher power outputs could impair mitochondrial fatty acid oxidation.
    Keywords:  CPT-I flux; Exercise; L-carnitine; Mitochondrial bioenergetics
    DOI:  https://doi.org/10.1042/BCJ20180849
  23. Cell. 2019 Jan 02. pii: S0092-8674(18)31517-4. [Epub ahead of print]
    The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier.
    Jonathan J Ruprecht, Martin S King, Thomas Zögg, Antoniya A Aleksandrova, Els Pardon, Paul G Crichton, Jan Steyaert, Edmund R S Kunji.
      Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family.
    Keywords:  adenine nucleotide translocase; adenine nucleotide translocator; alternating access mechanism; bioenergetics; bongkrekate; cardiolipin; induced fit; mitochondria; transport mechanism
    DOI:  https://doi.org/10.1016/j.cell.2018.11.025
  24. PLoS Comput Biol. 2019 Jan 07. 15(1): e1006719
    Calcium phosphate precipitation inhibits mitochondrial energy metabolism.
    Sathyavani Malyala, Yizhu Zhang, Jasiel O Strubbe, Jason N Bazil.
      Early studies have shown that moderate levels of calcium overload can cause lower oxidative phosphorylation rates. However, the mechanistic interpretations of these findings were inadequate. And while the effect of excessive calcium overload on mitochondrial function is well appreciated, there has been little to no reports on the consequences of low to moderate calcium overload. To resolve this inadequacy, mitochondrial function from guinea pig hearts was quantified using several well-established methods including high-resolution respirometry and spectrofluorimetry and analyzed using mathematical modeling. We measured key mitochondrial variables such as respiration, mitochondrial membrane potential, buffer calcium, and substrate effects for a range of mitochondrial calcium loads from near zero to levels approaching mitochondrial permeability transition. In addition, we developed a computer model closely mimicking the experimental conditions and used this model to design experiments capable of eliminating many hypotheses generated from the data analysis. We subsequently performed those experiments and determined why mitochondrial ADP-stimulated respiration is significantly lowered during calcium overload. We found that when calcium phosphate levels, not matrix free calcium, reached sufficient levels, complex I activity is inhibited, and the rate of ATP synthesis is reduced. Our findings suggest that calcium phosphate granules form physical barriers that isolate complex I from NADH, disrupt complex I activity, or destabilize cristae and inhibit NADH-dependent respiration.
    DOI:  https://doi.org/10.1371/journal.pcbi.1006719
  25. Metab Eng. 2019 Jan 04. pii: S1096-7176(18)30318-5. [Epub ahead of print]
    Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function.
    Zhengtao Liu, Cheng Zhang, Sunjae Lee, Woonghee Kim, Martina Klevstig, Azadeh M Harzandi, Natasa Sikanic, Muhammad Arif, Marcus Ståhlman, Jens Nielsen, Mathias Uhlen, Jan Boren, Adil Mardinoglu.
      The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of liver-specific genes including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis. We found that modulation of these genes effects the total triglycerides levels within the cells and viability of the cells. Next, we generated IN for HepG2 cells, identified reporter transcription factors based on IN and found that the modulation of these genes affects key metabolic pathways associated with lipid metabolism (steroid biosynthesis, PPAR signalling pathway, fatty acid synthesis and oxidation) and cancer development (DNA replication, cell cycle and p53 signalling) involved in the progression of NAFLD and HCC. Finally, we observed that inhibition of PKLR lead to decreased glucose uptake and decreased mitochondrial activity in HepG2 cells. Hence, our systems level analysis indicated that PKLR can be targeted for development efficient treatment strategy for NAFLD and HCC.
    DOI:  https://doi.org/10.1016/j.ymben.2019.01.001
  26. Front Oncol. 2018 ;8 622
    NAD Metabolism in Cancer Therapeutics.
    Keisuke Yaku, Keisuke Okabe, Keisuke Hikosaka, Takashi Nakagawa.
      Cancer cells have a unique energy metabolism for sustaining rapid proliferation. The preference for anaerobic glycolysis under normal oxygen conditions is a unique trait of cancer metabolism and is designated as the Warburg effect. Enhanced glycolysis also supports the generation of nucleotides, amino acids, lipids, and folic acid as the building blocks for cancer cell division. Nicotinamide adenine dinucleotide (NAD) is a co-enzyme that mediates redox reactions in a number of metabolic pathways, including glycolysis. Increased NAD levels enhance glycolysis and fuel cancer cells. In fact, nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme for NAD synthesis in mammalian cells, is frequently amplified in several cancer cells. In addition, Nampt-specific inhibitors significantly deplete NAD levels and subsequently suppress cancer cell proliferation through inhibition of energy production pathways, such as glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. NAD also serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD gylycohydrolase (CD38 and CD157); thus, NAD regulates DNA repair, gene expression, and stress response through these enzymes. Thus, NAD metabolism is implicated in cancer pathogenesis beyond energy metabolism and considered a promising therapeutic target for cancer treatment. In this review, we present recent findings with respect to NAD metabolism and cancer pathogenesis. We also discuss the current and future perspectives regarding the therapeutics that target NAD metabolic pathways.
    Keywords:  CD38; FK866; NAD; Nampt; Naprt; PARP; Warburg effect; sirtuin
    DOI:  https://doi.org/10.3389/fonc.2018.00622
  27. J Biol Chem. 2019 Jan 09. pii: jbc.AW119.003226. [Epub ahead of print]
    Nutrient Regulation of Signaling & Transcription.
    Gerald W Hart.
      In the early 1980s, while using purified glycosyltransferases to probe glycan structures on surfaces of living cells in the murine immune system, we discovered a novel form of serine/threonine protein glycosylation (O-linked b-N-acetylglucosamine; O-GlcNAc) that occurs on thousands of proteins within the nucleus, cytoplasm and mitochondria. Prior to this discovery, it was dogma that protein glycosylation was restricted to the luminal compartments of the secretory pathway and on extracellular domains of membrane and secretory proteins. Work in the last three decades from several laboratories has shown that O-GlcNAc cycling serves as a nutrient sensor to regulate signaling, transcription, mitochondrial activity and cytoskeletal functions. O-GlcNAc also has extensive crosstalk with phosphorylation, not only at the same or proximal site on polypeptides, but also by regulating each other's enzymes that catalyze cycling of the modifications. O-GlcNAc is generally not elongated or modified. It cycles on and off polypeptides in a time scale similar to phosphorylation, and both the enzyme that adds O-GlcNAc, the O-GlcNAc transferase (OGT), and the enzyme that removes O-GlcNAc (OGA) are highly conserved from C. elegans to humans. Both O-GlcNAc cycling enzymes are essential in mammals and plants. Due to O-GlcNAc's fundamental roles as a cellular nutrient and stress sensor, it plays an important role in the etiologies of chronic diseases of aging, including diabetes, cancer and neurodegenerative disease. This review will present an overview of our current understanding of O-GlcNAc's regulation, functions and roles in chronic diseases of aging.
    Keywords:  Alzheimer disease; O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc); O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); cancer; diabetes; neurodegeneration; phosphorylation
    DOI:  https://doi.org/10.1074/jbc.AW119.003226
  28. Mol Nutr Food Res. 2019 Jan 10. e1801322
    Increased Dynamin-Related Protein 1-Dependent Mitochondrial Fission Contributes to High-Fat Diet-Induced Cardiac Dysfunction and Insulin Resistance by Elevating Tafazzin in Mouse Hearts.
    Wenguang Chang, Dandan Xiao, Xiang Ao, Mengyang Li, Tao Xu, Jianxun Wang.
       SCOPE: High-fat diet-induced insulin resistance is a major contributor to the pathogenesis of cardiovascular diseases. However, the molecular mechanisms that regulate cardiac insulin signalling are not fully understood. We investigated the regulatory role of tafazzin in the hearts of high-fat diet-fed mice.
    METHODS AND RESULTS: Mice were fed a high-fat diet (HF) or a low-fat diet (LF) for up to 24 weeks. After 24 weeks, we found that high-fat diet-induced cardiac dysfunction is linked to overexpression of the mitochondrial protein tafazzin. Increased tafazzin promotes mitochondrial fission and impairs insulin signalling, which is mediated by dynamin-related protein 1 (Drp-1) translocation from the cytosol to the mitochondria. Furthermore, knockdown of tafazzin with siRNA inhibited palmitic acid-induced mitochondrial fission and restored insulin sensitivity. Moreover, we identified miR-125b-5p as an upstream regulator targeting tafazzin and further rescued palmitate-induced insulin resistance.
    CONCLUSION: In high-fat diet-fed mouse hearts, increased tafazzin contributes to insulin resistance via mediating Drp-1 translocation to the mitochondria, and a small non-coding RNA, miR-125b-5p, at least partially regulates this signalling pathway and alleviates insulin resistance. This article is protected by copyright. All rights reserved.
    Keywords:  high-fat diet; insulin resistance; miR-125b; tafazzin
    DOI:  https://doi.org/10.1002/mnfr.201801322
  29. Immunity. 2018 Dec 23. pii: S1074-7613(18)30525-9. [Epub ahead of print]
    The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons.
    Brian P Daniels, Sigal B Kofman, Julian R Smith, Geoffrey T Norris, Annelise G Snyder, Joseph P Kolb, Xia Gao, Jason W Locasale, Jennifer Martinez, Michael Gale, Yueh-Ming Loo, Andrew Oberst.
      As long-lived post-mitotic cells, neurons employ unique strategies to resist pathogen infection while preserving cellular function. Here, using a murine model of Zika virus (ZIKV) infection, we identified an innate immune pathway that restricts ZIKV replication in neurons and is required for survival upon ZIKV infection of the central nervous system (CNS). We found that neuronal ZIKV infection activated the nucleotide sensor ZBP1 and the kinases RIPK1 and RIPK3, core components of virus-induced necroptotic cell death signaling. However, activation of this pathway in ZIKV-infected neurons did not induce cell death. Rather, RIPK signaling restricted viral replication by altering cellular metabolism via upregulation of the enzyme IRG1 and production of the metabolite itaconate. Itaconate inhibited the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. These findings demonstrate an immunometabolic mechanism of viral restriction during neuroinvasive infection.
    DOI:  https://doi.org/10.1016/j.immuni.2018.11.017
  30. Biochem J. 2019 Jan 07. 476(1): 25-37
    Strangers in strange lands: mitochondrial proteins found at extra-mitochondrial locations.
    David P Scanlon, Michael W Salter.
      The mitochondrial proteome is estimated to contain ∼1100 proteins, the vast majority of which are nuclear-encoded, with only 13 proteins encoded by the mitochondrial genome. The import of these nuclear-encoded proteins into mitochondria was widely believed to be unidirectional, but recent discoveries have revealed that many these 'mitochondrial' proteins are exported, and have extra-mitochondrial activities divergent from their mitochondrial function. Surprisingly, three of the exported proteins discovered thus far are mitochondrially encoded and have significantly different extra-mitochondrial roles than those performed within the mitochondrion. In this review, we will detail the wide variety of proteins once thought to only reside within mitochondria, but now known to 'emigrate' from mitochondria in order to attain 'dual citizenship', present both within mitochondria and elsewhere.
    Keywords:  cellular localisation; mitochondria; mtDNA; multifunctional proteins; trafficking; transport
    DOI:  https://doi.org/10.1042/BCJ20180473
  31. Front Oncol. 2018 ;8 632
    Glutaminolysis Mediated by MALT1 Protease Activity Facilitates PD-L1 Expression on ABC-DLBCL Cells and Contributes to Their Immune Evasion.
    Xichun Xia, Wei Zhou, Chengbin Guo, Zhen Fu, Leqing Zhu, Peng Li, Yan Xu, Liangyan Zheng, Hua Zhang, Changliang Shan, Yunfei Gao.
      Previous studies have demonstrated that programmed death-1 ligand 1 (PD-L1) expressed in an aggressive activated B-cell (ABC)/non-germinal center B cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) is associated with inhibition of the tumor-associated T cell response. However, the molecular mechanism underlying PD-L1 expression in ABC-DLBCL remains unclear. Here, we report that MALT1 protease activity is required for ABC-DLBCL cells to evade cytotoxity of Vγ9Vδ2 T lymphocytes by generating substantial PD-L1+ ABC-DLBCL cells. While, NF-κB was dispensable for the PD-L1 expression induced by MALT1 protease activity in ABC-DLBCL cells. Furthermore, we showed that GLS1 expression was profoundly reduced by MALT1 protease activity inhibition, which resulted in insufficiency of glutaminolysis-derived mitochondrial bioenergetics. Activation of the PD-L1 transcription factor STAT3, which was strongly suppressed by glutaminolysis blockade, was rescued in a TCA (tricarboxylic acid) cycle-dependent manner by glutamate addition. Collectively, MALT1 protease activity coupled with glutaminolysis-derived mitochondrial bioenergetics plays an essential role in PD-L1 expression on ABC-DLBCL cells under immunosurveillance stress. Thus, our research sheds light on a mechanism underlying PD-L1 expression and highlights a potential therapeutic target to vanquish immune evasion by ABC-DLBCL cells.
    Keywords:  MALT1 protease activity; PD-L1; diffuse large B-cell lymphoma; glutaminolysis; immune evasion
    DOI:  https://doi.org/10.3389/fonc.2018.00632
  32. Cancer Discov. 2019 Jan 09. pii: CD-18-0567. [Epub ahead of print]
    Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis.
    Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney Campbell, Robert J Norgard, Kollin C Schultz, Simone Sidoli, Joshua L D Parris, Hayley C Affronti, Sharanya Sivanand, Shaun Egolf, Yogev Sela, Marco Trizzino, Alessandro Gardini, Benjamin A Garcia, Nathaniel W Snyder, Ben Z Stanger, Kathryn Wellen.
      Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Since acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anti-cancer effects.
    DOI:  https://doi.org/10.1158/2159-8290.CD-18-0567
  33. Neoplasia. 2019 Jan 07. pii: S1476-5586(18)30575-X. [Epub ahead of print]21(2): 230-238
    Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2+/- Mice.
    Ashley T Jones, Kalin Narov, Jian Yang, Julian R Sampson, Ming Hong Shen.
      Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to glucose and glutamine in Tsc1-/-or Tsc2-/- mouse embryonic fibroblasts (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic inhibition causes significant cell death in Tsc2-/- but not Tsc2+/+ MEFs. In this study, we tested efficacy of dual inhibition of glycolysis with 3-BrPA and glutaminolysis with CB-839 for renal tumors in Tsc2+/- mice. Following 2 months of treatment of Tsc2+/- mice from the age of 12 months, combination of 3-BrPA and CB-839 significantly reduced overall size and cellular areas of all renal lesions (cystic/papillary adenomas and solid carcinomas), but neither alone did. Combination of 3-BrPA and CB-839 inhibited mTORC1 and the proliferation of tumor cells but did not increase apoptosis. However, combination of 3-BrPA and CB-839 was not as efficacious as rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 for renal lesions of Tsc2+/- mice. Consistently, rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 had stronger inhibitory effects on mTORC1 and proliferation of tumor cells than combination of 3-BrPA and CB-839. We conclude that combination of 3-BRPA and CB-839 may not offer a better therapeutic strategy than rapamycin for TSC-associated tumors.
    DOI:  https://doi.org/10.1016/j.neo.2018.12.003
  34. Sci Adv. 2019 Jan;5(1): eaau7314
    Improving the metabolic fidelity of cancer models with a physiological cell culture medium.
    Johan Vande Voorde, Tobias Ackermann, Nadja Pfetzer, David Sumpton, Gillian Mackay, Gabriela Kalna, Colin Nixon, Karen Blyth, Eyal Gottlieb, Saverio Tardito.
      Currently available cell culture media may not reproduce the in vivo metabolic environment of tumors. To demonstrate this, we compared the effects of a new physiological medium, Plasmax, with commercial media. We prove that the disproportionate nutrient composition of commercial media imposes metabolic artifacts on cancer cells. Their supraphysiological concentrations of pyruvate stabilize hypoxia-inducible factor 1α in normoxia, thereby inducing a pseudohypoxic transcriptional program. In addition, their arginine concentrations reverse the urea cycle reaction catalyzed by argininosuccinate lyase, an effect not observed in vivo, and prevented by Plasmax in vitro. The capacity of cancer cells to form colonies in commercial media was impaired by lipid peroxidation and ferroptosis and was rescued by selenium present in Plasmax. Last, an untargeted metabolic comparison revealed that breast cancer spheroids grown in Plasmax approximate the metabolic profile of mammary tumors better. In conclusion, a physiological medium improves the metabolic fidelity and biological relevance of in vitro cancer models.
    DOI:  https://doi.org/10.1126/sciadv.aau7314
  35. Cold Spring Harb Perspect Biol. 2019 Jan 07. pii: a033944. [Epub ahead of print]
    Signaling and Regulation of the Mitochondrial Unfolded Protein Response.
    Nandhitha Uma Naresh, Cole M Haynes.
      The mitochondrial proteome encompasses more than a thousand proteins, which are encoded by the mitochondrial and nuclear genomes. Mitochondrial biogenesis and network health relies on maintenance of protein import pathways and the protein-folding environment. Cell-extrinsic or -intrinsic stressors that challenge mitochondrial proteostasis negatively affect organellar function. During conditions of stress, cells use impaired protein import as a sensor for mitochondrial dysfunction to activate a stress response called the mitochondrial unfolded protein response (UPRmt). UPRmt activation leads to an adaptive transcriptional program that promotes mitochondrial recovery, metabolic adaptations, and innate immunity. In this review, we discuss the regulation of UPRmt activation as well as its role in maintaining mitochondrial homeostasis in physiological and pathological scenarios.
    DOI:  https://doi.org/10.1101/cshperspect.a033944
  36. Int J Mol Sci. 2019 Jan 09. pii: E238. [Epub ahead of print]20(2):
    HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance.
    Ayako Nagao, Minoru Kobayashi, Sho Koyasu, Christalle C T Chow, Hiroshi Harada.
      Normal cells produce adenosine 5'-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.
    Keywords:  HIF-1; cancer; glucose metabolism; hypoxia
    DOI:  https://doi.org/10.3390/ijms20020238
  37. Nat Rev Immunol. 2019 Jan 08.
    Calcium signalling in T cells.
    Mohamed Trebak, Jean-Pierre Kinet.
      Calcium (Ca2+) signalling is of paramount importance to immunity. Regulated increases in cytosolic and organellar Ca2+ concentrations in lymphocytes control complex and crucial effector functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity. Altered Ca2+ regulation in lymphocytes leads to various autoimmune, inflammatory and immunodeficiency syndromes. Several types of plasma membrane and organellar Ca2+-permeable channels are functional in T cells. They contribute highly localized spatial and temporal Ca2+ microdomains that are required for achieving functional specificity. While the mechanistic details of these Ca2+ microdomains are only beginning to emerge, it is evident that through crosstalk, synergy and feedback mechanisms, they fine-tune T cell signalling to match complex immune responses. In this article, we review the expression and function of various Ca2+-permeable channels in the plasma membrane, endoplasmic reticulum, mitochondria and endolysosomes of T cells and their role in shaping immunity and the pathogenesis of immune-mediated diseases.
    DOI:  https://doi.org/10.1038/s41577-018-0110-7
  38. Front Endocrinol (Lausanne). 2018 ;9 753
    Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences.
    Eric Fontaine.
      Metformin is the most widely prescribed drug to treat patients with type II diabetes, for whom retrospective studies suggest that metformin may have anticancer properties. However, in experiments performed with isolated cells, authors have reported both pro- and anti-apoptotic effects of metformin. The exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 17,000 articles in PubMed. Among the various widely recognized or recently proposed targets, it has been reported consistently that metformin is capable of inhibiting mitochondrial respiratory chain Complex I. Since most of the effects of metformin have been replicated by other inhibitors of Complex I, it has been suggested that the mechanism of action of metformin involved the inhibition of Complex I. However, compared to conventional Complex I inhibitors, the metformin-induced inhibition of Complex I has unique characteristics. Among these, the most original one is that the concentrations of metformin required to inhibit Complex I are lower in intact cells than in isolated mitochondria. Experiments with isolated mitochondria or Complex I were generally performed using millimolar concentrations of metformin, while plasma levels remain in the micromolar range in both human and animal studies, highlighting that metformin concentration is an important issue. In order to explain the effects in animals based on observations in cells and mitochondria, some authors proposed a direct effect of the drug on Complex I involving an accumulation of metformin inside the mitochondria while others proposed an indirect effect (the drug no longer having to diffuse into the mitochondria). This brief review attempts to: gather arguments for and against each hypothesis concerning the mechanism by which metformin inhibits Complex I and to highlight remaining questions about the toxicity mechanism of metformin for certain cancer cells.
    Keywords:  Complex I; cancer; cell death; metformin; mitochondria; permeability transition; pharmacokinetic
    DOI:  https://doi.org/10.3389/fendo.2018.00753
  39. Nat Commun. 2019 Jan 10. 10(1): 130
    Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
    Nicola Ferrari, Romana Ranftl, Ievgeniia Chicherova, Neil D Slaven, Emad Moeendarbary, Aaron J Farrugia, Maxine Lam, Maria Semiannikova, Marie C W Westergaard, Julia Tchou, Luca Magnani, Fernando Calvo.
      Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.
    DOI:  https://doi.org/10.1038/s41467-018-07987-0
  40. Hum Mol Genet. 2019 Jan 09.
    Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study.
    Jaakko Laaksonen, Ilkka Seppälä, Emma Raitoharju, Nina Mononen, Leo-Pekka Lyytikäinen, Melanie Waldenberger, Thomas Illig, Maija Lepistö, Henrikki Almusa, Pekka Ellonen, Nina Hutri-Kähönen, Markus Juonala, Mika Kähönen, Olli Raitakari, Jukka T Salonen, Terho Lehtimäki.
       BACKGROUND: The effect of mitochondrial DNA variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mitochondrial DNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial SNPs (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects.
    METHODS: The genome-wide blood cell expression data of 19,637 probes, 199 deep-sequenced mtSNPs, and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis.
    RESULTS: Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects.
    CONCLUSIONS: This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.
    DOI:  https://doi.org/10.1093/hmg/ddz011
  41. Nat Commun. 2019 Jan 09. 10(1): 91
    Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin.
    A Flores, S Sandoval-Gonzalez, R Takahashi, A Krall, L Sathe, L Wei, C Radu, J Jolly, N Graham, H R Christofk, W E Lowry.
      Although numerous therapeutic strategies have attempted to target aerobic glycolysis to inhibit tumor progression, these approaches have not resulted in effective clinical outcomes. Murine squamous cell carcinoma (SCC) can be initiated by hair follicle stem cells (HFSCs). HFSCs utilize aerobic glycolysis, and the activity of lactate dehydrogenase (Ldh) is essential for HFSC activation. We sought to determine whether Ldh activity in SCC is critical for tumorigenesis or simply a marker of the cell type of origin. Genetic abrogation or induction of Ldh activity in HFSC-mediated tumorigenesis shows no effect on tumorigenesis as measured by number, time to formation, proliferation, volume, epithelial to mesenchymal transition, gene expression, or immune response. Ldha-null tumors show dramatically reduced levels of glycolytic metabolites by metabolomics, and significantly reduced glucose uptake by FDG-PET live animal imaging. These results suggest that squamous cancer cells of origin do not require increased glycolytic activity to generate cancers.
    DOI:  https://doi.org/10.1038/s41467-018-07857-9
  42. Cell. 2018 Dec 28. pii: S0092-8674(18)31563-0. [Epub ahead of print]
    METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
    Shuo Liu, Simone Hausmann, Scott Moore Carlson, Mary Esmeralda Fuentes, Joel William Francis, Renjitha Pillai, Shane Michael Lofgren, Laura Hulea, Kristofferson Tandoc, Jiuwei Lu, Ami Li, Nicholas Dang Nguyen, Marcello Caporicci, Michael Paul Kim, Anirban Maitra, Huamin Wang, Ignacio Ivan Wistuba, John Anthony Porco, Michael Cory Bassik, Joshua Eric Elias, Jikui Song, Ivan Topisirovic, Capucine Van Rechem, Pawel Karol Mazur, Or Gozani.
      Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
    Keywords:  METTL13; RAS; eEF1A; lung cancer; lysine methylation; pancreatic cancer; protein methylation; translation; translation elongation
    DOI:  https://doi.org/10.1016/j.cell.2018.11.038
  43. Cell Metab. 2018 Dec 21. pii: S1550-4131(18)30748-4. [Epub ahead of print]
    AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth.
    Krushna C Patra, Vajira K Weerasekara, Nabeel Bardeesy.
      Cancer cells must adapt to metabolic stress during tumor progression. In this issue of Cell Metabolism, Eichner et al. (2019) report that lung cancer development in genetically engineered mice requires the energy sensor AMP-activated protein kinase (AMPK). Their findings suggest that AMPK-mediated induction of lysosomal function supports cancer cell fitness, particularly during the early stages of tumorigenesis.
    DOI:  https://doi.org/10.1016/j.cmet.2018.12.011
  44. Cell. 2019 Jan 10. pii: S0092-8674(18)31627-1. [Epub ahead of print]176(1-2): 73-84.e15
    Spatially Stable Mitochondrial Compartments Fuel Local Translation during Plasticity.
    Vidhya Rangaraju, Marcel Lauterbach, Erin M Schuman.
      Local translation meets protein turnover and plasticity demands at synapses, however, the location of its energy supply is unknown. We found that local translation in neurons is powered by mitochondria and not by glycolysis. Super-resolution microscopy revealed that dendritic mitochondria exist as stable compartments of single or multiple filaments. To test if these mitochondrial compartments can serve as local energy supply for synaptic translation, we stimulated individual synapses to induce morphological plasticity and visualized newly synthesized proteins. Depletion of local mitochondrial compartments abolished both the plasticity and the stimulus-induced synaptic translation. These mitochondrial compartments serve as spatially confined energy reserves, as local depletion of a mitochondrial compartment did not affect synaptic translation at remote spines. The length and stability of dendritic mitochondrial compartments and the spatial functional domain were altered by cytoskeletal disruption. These results indicate that cytoskeletally tethered local energy compartments exist in dendrites to fuel local translation during synaptic plasticity.
    Keywords:  ATP; compartments; cytoskeleton; energy; local translation; mitochondria; nascent protein; protein synthesis; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.cell.2018.12.013
  45. Front Immunol. 2018 ;9 3020
    Natural Killer Cell Education Is Associated With a Distinct Glycolytic Profile.
    Caroline Pfeifer, Andrew J Highton, Sven Peine, Jürgen Sauter, Alexander H Schmidt, Madeleine J Bunders, Marcus Altfeld, Christian Körner.
      NK cells expressing self-inhibitory receptors display increased functionality compared to NK cells lacking those receptors. The acquisition of functional competence in these particular NK-cell subsets is termed education. Little is known about the underlying mechanisms that lead to the functional differences between educated and uneducated NK cells. An increasing number of studies suggest that cellular metabolism is a determinant of immune cell functions. Thus, alterations in cellular metabolic pathways may play a role in the process of NK-cell education. Here, we compared the glycolytic profile of educated and uneducated primary human NK cells. KIR-educated NK cells showed significantly increased expression levels of the glucose transporter Glut1 in comparison to NKG2A-educated or uneducated NK cells with and without exposure to target cells. Subsequently, the metabolic profile of NK-cell subsets was determined using a Seahorse XF Analyzer. Educated NK cells displayed significantly higher rates of cellular glycolysis than uneducated NK cells even in a resting state. Our results indicate that educated and uneducated NK cells reside in different metabolic states prior to activation. These differences in the ability to utilize glucose may represent an underlying mechanism for the superior functionality of educated NK cells expressing self-inhibitory receptors.
    Keywords:  Glut1; HLA class I; NK-cell education; cytotoxicity; glycolysis; killer-cell immunoglobulin-like receptor (KIR); metabolism
    DOI:  https://doi.org/10.3389/fimmu.2018.03020
  46. J Mol Cell Cardiol. 2019 Jan 06. pii: S0022-2828(18)30918-0. [Epub ahead of print]
    Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo.
    Sundararajan Venkatesh, Min Li, Toshiro Saito, Mingming Tong, Eman Rashed, Satvik Mareedu, Peiyong Zhai, Clea Bárcena, Carlos López-Otín, Ghassan Yehia, Junichi Sadoshima, Carolyn K Suzuki.
       RATIONALE: LonP1 is an essential mitochondrial protease, which is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. However, the importance of LonP1 during cardiac stress is largely unknown.
    OBJECTIVE: To determine the functions of LonP1 during ischemia/reperfusion (I/R) injury in vivo, and hypoxia-reoxygenation (H/R) stress in vitro.
    METHODS AND RESULTS: LonP1 was induced 2-fold in wild-type mice during cardiac ischemic preconditioning (IPC), which protected the heart against ischemia-reperfusion (I/R) injury. In contrast, haploinsufficiency of LonP1 (LONP1+/-) abrogated IPC-mediated cardioprotection. Furthermore, LONP1+/- mice showed significantly increased infarct size after I/R injury, whereas mice with 3-4 fold cardiac-specific overexpression of LonP1 (LonTg) had substantially smaller infarct size and reduced apoptosis compared to wild-type controls. To investigate the mechanisms underlying cardioprotection, LonTg mice were subjected to ischemia (45 min) followed by short intervals of reperfusion (10, 30, 120 min). During early reperfusion, the left ventricles of LonTg mice showed substantially reduced oxidative protein damage, maintained mitochondrial redox homeostasis, and showed a marked downregulation of both Complex I protein level and activity in contrast to NTg mice. Conversely, when LonP1 was knocked down in isolated neonatal rat ventricular myocytes (NRVMs), an up-regulation of Complex I subunits and electron transport chain (ETC) activities was observed, which was associated with increased superoxide production and reduced respiratory efficiency. The knockdown of LonP1 in NRVMs caused a striking dysmorphology of the mitochondrial inner membrane, mitochondrial hyperpolarization and increased hypoxia-reoxygenation (H/R)-activated apoptosis. Whereas, LonP1 overexpression blocked H/R-induced cell death.
    CONCLUSIONS: LonP1 is an endogenous mediator of cardioprotection. Our findings show that upregulation of LonP1 mitigates cardiac injury by preventing oxidative damage of proteins and lipids, preserving mitochondrial redox balance and reprogramming bioenergetics by reducing Complex I content and activity. Mechanisms that promote the upregulation of LonP1 could be beneficial in protecting the myocardium from cardiac stress and limiting I/R injury.
    Keywords:  Cardioprotection; Ischemia and reperfusion; LonP1 protease; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.yjmcc.2018.12.017
  47. Nature. 2019 Jan;565(7738): 167-168
    Fat cells with a sweet tooth.
    Wenfei Sun, Christian Wolfrum.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-018-07739-6
  48. Proteomics. 2019 Jan 11. e1800301
    Analyzing cysteine site neighbors in proteins to reveal dimethyl fumarate targets.
    Arianna Carolina Rosa, Elisa Benetti, Margherita Gallicchio, Valentina Boscaro, Luigi Cangemi, Chiara Dianzani, Gianluca Miglio.
      This work proposes a novel approach by which to consistently classify cysteine sites in proteins in terms of their reactivity toward dimethyl fumarate (DMF) and fumarate. Dimethyl fumarate-based drug products have been approved for use as oral treatments for psoriasis and relapsing-remitting multiple sclerosis. The adduction of DMF and its (re)active metabolites to certain cysteine residues in proteins is thought to underlie their effects. However, only a few receptors for these compounds have been discovered to date. Our approach takes advantage of the growing number of known DMF- and fumarate-sensitive proteins and sites to perform analyses by combining the concepts of network theory, for protein structure analyses, and machine learning procedures. Wide-ranging and previously unforeseen variety was found in the analysis of the neighborhood composition (the first neighbors) of cysteine sites found in DMF- and fumarate-sensitive proteins. Furthermore, neighborhood composition has shown itself to be a network-type attribute that is endowed with remarkable predictive power when distinct classification algorithms are employed. In conclusion, when adopted in combination with other target identification/validation approaches, methods that are based on the analysis of cysteine site neighbors in proteins should provide useful information by which to decipher the mode of action of DMF-based drugs. This article is protected by copyright. All rights reserved.
    Keywords:  Cysteine reactivity; computational method; machine learning; residue interaction network
    DOI:  https://doi.org/10.1002/pmic.201800301
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